vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/vjgb-25-74vavilov-4756Research ArticleМЕДИЦИНСКАЯ ГЕНЕТИКАMEDICAL GENETICSРедкие миссенс-замены в генах митохондриальной ДНК у пациентов с желудочковыми тахикардиямиRare missense substitutions in the mitochondrial DNA genes in patients with ventricular tachycardiahttps://orcid.org/0000-0002-7692-9954ГолубенкоМ. В.GolubenkoM. V.

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maria-golubenko@medgenetics.ruhttps://orcid.org/0000-0001-6133-8986БабушкинаН. П.BabushkinaN. P.

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https://orcid.org/0000-0002-2818-1419КорепановВ. А.KorepanovV. A.

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https://orcid.org/0000-0001-7969-7020ВалиахметовН. Р.ValiakhmetovN. R.

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https://orcid.org/0000-0003-2645-4142АтабековТ. А.AtabekovT. A.

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https://orcid.org/0000-0002-2629-6466ВиттК. Н.VittK. N.

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https://orcid.org/0000-0001-6568-6339ЗарубинА. А.ZarubinA. A.

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https://orcid.org/0000-0002-0719-9732МакееваО. А.MakeevaO. A.

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https://orcid.org/0000-0001-6066-3998АфанасьевС. А.AfanasievS. A.

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https://orcid.org/0000-0003-1415-3932БаталовР. Е.BatalovR. E.

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https://orcid.org/0000-0002-9488-6900ГарганееваА. А.GarganeevaA. A.

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https://orcid.org/0000-0002-0673-4094НазаренкоМ. С.NazarenkoM. S.

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https://orcid.org/0000-0002-2113-4556ПузырёвВ. П.PuzyrevV. P.

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Научно-исследовательский институт медицинской генетики Томского национального исследовательского медицинского центра Российской академии наукРоссияResearch Institute of Medical Genetics, Tomsk National Research Medical Center of the Russian Academy of SciencesRussian FederationНаучно-исследовательский институт кардиологии Томского национального исследовательского медицинского центра Российской академии наукРоссияCardiology Research Institute, Tomsk National Research Medical Center of the Russian Academy of SciencesRussian Federation202504092025295676684Copyright © Голубенко М.В., Бабушкина Н.П., Корепанов В.А., Валиахметов Н.Р., Атабеков Т.А., Витт К.Н., Зарубин А.А., Макеева О.А., Афанасьев С.А., Баталов Р.Е., Гарганеева А.А., Назаренко М.С., Пузырёв В.П., 20252025Голубенко М.В., Бабушкина Н.П., Корепанов В.А., Валиахметов Н.Р., Атабеков Т.А., Витт К.Н., Зарубин А.А., Макеева О.А., Афанасьев С.А., Баталов Р.Е., Гарганеева А.А., Назаренко М.С., Пузырёв В.П.Golubenko M.V., Babushkina N.P., Korepanov V.A., Valiakhmetov N.R., Atabekov T.A., Vitt K.N., Zarubin A.A., Makeeva O.A., Afanasiev S.A., Batalov R.E., Garganeeva A.A., Nazarenko M.S., Puzyrev V.P.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/4756

   Митохондриальная ДНК (мтДНК) характеризуется высоким полиморфизмом в популяциях. При этом некоторые патогенные варианты мтДНК могут приводить к развитию наследственных митохондриальных синдромов, симптоматика которых включает в том числе нарушения ритма сердца. С другой стороны, жизнеугрожающие аритмии, в виде желудочковой тахикардии, являются фактором риска внезапной смерти у пациентов с сердечно-сосудистыми заболеваниями.

   Целью работы стало исследование редких («приватных») миссенс-замен в мтДНК пациентов с зарегистрированными эпизодами желудочковой тахикардии в анамнезе в сравнении с пациентами с ишемической болезнью сердца без жизнеугрожающих нарушений ритма и индивидами без клинических проявлений сердечно-сосудистых заболеваний.

   Определение последовательности мтДНК проводили с помощью методов высокопроизводительного секвенирования, для оценки эффекта миссенс-замен использовали специализированные алгоритмы-предикторы эффекта генных вариантов. Сравнительный анализ спектра выявленных аминокислотных замен в исследованных группах показал, что во всех трех группах около 40 % индивидов были носителями «приватных» миссенс-вариантов в мтДНК, однако среди них в группе пациентов с нарушениями сердечного ритма чаще встречались варианты, классифицируемые предиктором APOGEE2 как «варианты неопределенного значения» (VUS), по сравнению с контрольной группой, в которой «приватных» миссенс-замен категории VUS не обнаружено (p = 0.0063 для точного критерия Фишера). Кроме того, группы различались по значениям phred-ранжированных значений CADD (Combined Annotation Dependent Depletion), которые были ниже для индивидов из контрольной группы. Полученные результаты указывают на то, что редкие варианты мтДНК могут вносить вклад в предрасположенность к сердечно-сосудистым заболеваниям, в частности в риск развития желудочковой тахикардии у некоторых пациентов.

   Human mitochondrial DNA (mtDNA) exhibits high population-level polymorphism. While certain pathogenic mtDNA variants are known to cause hereditary mitochondrial syndromes, often presenting with cardiac arrhythmias, life-threatening ventricular tachycardia (VT) itself is a major risk factor for sudden death in cardiovascular diseases.

   The aim of the work was to study rare (“private”) missense substitutions in the mtDNA of patients with documented episodes of ventricular tachycardia in comparison with patients with ischemic heart disease without life-threatening heart arrhythmias and individuals without clinical manifestations of cardiovascular diseases.

   The sequencing of mtDNA was performed using high-throughput sequencing methods. Specialized algorithms predicting the effect of gene variants were used to assess the effect of missense substitutions. Comparative analysis of the spectrum of the identified amino acid substitutions in the studied groups showed that about 40 % of the individuals in all three groups were carriers of “private” missense variants in mtDNA. However, among such substitutions, the variants classified by the APOGEE2 predictor as “variants of uncertain significance” (VUS) were more common in the group of patients with heart arrhythmias than in the control group, where “private” missense substitutions of the VUS category were not detected (p = 0.0063 for Fisher’s exact test). In addition, the groups differed in their phred-ranked Combined Annotation Dependent Depletion (CADD) scores, which were lower for individuals in the control group. The results indicate that rare mtDNA variants may contribute to predisposition to cardiovascular disease – in particular, to the risk of developing ventricular tachycardia by some patients.

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The authors declare that there are no conflicts of interest present.